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1.
J Cereb Blood Flow Metab. 2018 May 23:271678X18776820. doi: 10.1177/0271678X18776820. [Epub ahead of print]

Towards quantitative [18F]FDG-PET/MRI of the brain: Automated MR-driven calculation of an image-derived input function for the non-invasive determination of cerebral glucose metabolic rates.

Author information

1
1 QIMP Group, Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.
2
2 Department of Radiology, Wayne State University School of Medicine, The Detroit Medical Center, Children's Hospital of Michigan, Detroit, MI, USA.
3
3 Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
4
4 Division of Nuclear Medicine, Department of Biomedical imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria.
5
5 Institute for Radiology and Nuclear Medicine, Stadtspital Waid Zurich, Zurich, Switzerland.
6
6 Department of Neurology, Medical University of Vienna, Vienna, Austria.

Abstract

Absolute quantification of PET brain imaging requires the measurement of an arterial input function (AIF), typically obtained invasively via an arterial cannulation. We present an approach to automatically calculate an image-derived input function (IDIF) and cerebral metabolic rates of glucose (CMRGlc) from the [18F]FDG PET data using an integrated PET/MRI system. Ten healthy controls underwent test-retest dynamic [18F]FDG-PET/MRI examinations. The imaging protocol consisted of a 60-min PET list-mode acquisition together with a time-of-flight MR angiography scan for segmenting the carotid arteries and intermittent MR navigators to monitor subject movement. AIFs were collected as the reference standard. Attenuation correction was performed using a separate low-dose CT scan. Assessment of the percentage difference between area-under-the-curve of IDIF and AIF yielded values within ±5%. Similar test-retest variability was seen between AIFs (9 ± 8) % and the IDIFs (9 ± 7) %. Absolute percentage difference between CMRGlc values obtained from AIF and IDIF across all examinations and selected brain regions was 3.2% (interquartile range: (2.4-4.3) %, maximum < 10%). High test-retest intravariability was observed between CMRGlc values obtained from AIF (14%) and IDIF (17%). The proposed approach provides an IDIF, which can be effectively used in lieu of AIF.

KEYWORDS:

Brain imaging; [18F]FDG; cerebral metabolic rates; image-derived input function; integrated PET/MRI

2.
Photoacoustics. 2018 Feb 2;10:1-19. doi: 10.1016/j.pacs.2018.01.003. eCollection 2018 Jun.

Neonatal brain resting-state functional connectivity imaging modalities.

Author information

1
CIPCE, School of Electrical and Computer Engineering, College of Engineering, University of Tehran, Tehran, Iran.
2
Departments of Radiology and Research Administration, Henry Ford Health System, Detroit, MI, USA.
3
Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA.
4
INSERM, U1105, Université de Picardie, CURS, F80036, Amiens, France.
5
INSERM U1105, Exploration Fonctionnelles du Système Nerveux Pédiatrique, South University Hospital, F80054, Amiens Cedex, France.
6
Laureate Institute for Brain Research, Tulsa, OK, USA.
7
Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
8
Department of Radiology, Wayne State University School of Medicine, Detroit, MI, USA.
9
Boston Children's Hospital, Department of Medicine, Harvard Medical School, Boston, MA, USA.
10
Molecular Imaging Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
11
Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA.

Abstract

Infancy is the most critical period in human brain development. Studies demonstrate that subtle brain abnormalities during this state of life may greatly affect the developmental processes of the newborn infants. One of the rapidly developing methods for early characterization of abnormal brain development is functional connectivity of the brain at rest. While the majority of resting-state studies have been conducted using magnetic resonance imaging (MRI), there is clear evidence that resting-state functional connectivity (rs-FC) can also be evaluated using other imaging modalities. The aim of this review is to compare the advantages and limitations of different modalities used for the mapping of infants' brain functional connectivity at rest. In addition, we introduce photoacoustic tomography, a novel functional neuroimaging modality, as a complementary modality for functional mapping of infants' brain.

KEYWORDS:

Infants; Neonatal brain; Neuroimaging modalities; Photoacoustic tomography; Resting-state functional connectivity

Publication type

Publication type

3.
Neuroimage. 2018 May 15;172:632-641. doi: 10.1016/j.neuroimage.2018.01.067. Epub 2018 Feb 10.

"Brain over body"-A study on the willful regulation of autonomic function during cold exposure.

Author information

1
Departments of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48201, USA; Departments of Radiology, Wayne State University School of Medicine, Detroit, MI 48201, USA. Electronic address: otto@pet.wayne.edu.
2
TKR Research and Consulting, LLC, Detroit 48201 USA.
3
Departments of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.

Abstract

The defense of body temperature against environmental thermal challenges is a core objective of homeostatic regulation governed by the autonomic nervous system. Autonomous mechanisms of thermoregulation are only weakly affected by top-down modulation, allowing only transient tolerance for extreme cold. There is however, anecdotal evidence of a unique set of individuals known for extreme cold tolerance. Here we present a case study of a 57-year old Dutch national, Wim Hof, the so-called "Iceman", with the ability to withstand frequent prolonged periods of extreme cold exposure based on the practice of a self-developed technique involving a combination of forced breathing, cold exposure and meditation (collectively referred to as the Wim Hof Method, henceforth "WHM"). The relative contributions of the brain and the periphery that endow the Iceman with these capabilities is unknown. To investigate this, we conducted multi-modal imaging assessments of the brain and the periphery using a combination of fMRI and PET/CT imaging. Thermoregulatory defense was evoked by subjecting the Iceman (and a cohort of typical controls) to a fMRI paradigm designed to generate periods of mild hypothermia interspersed by periods of return to basal core body temperature. fMRI was acquired in two separate sessions: in a typical (passive) state and following the practice of WHM. In addition, the Iceman also underwent a whole body PET/CT imaging session using the tracers C11-hydroxyephedrine (HED) and 18F-fluorodeoxyglucose (FDG) during both thermoneutral and prolonged mild cold conditions. This acquisition allowed us to determine changes in sympathetic innervation (HED) and glucose consumption (FDG) in muscle and fat tissues in the absence of the WHM. fMRI analyses indicated that the WHM activates primary control centers for descending pain/cold stimuli modulation in the periaqueductal gray (PAG), possibly initiating a stress-induced analgesic response. In addition, the WHM also engages higher-order cortical areas (left anterior and right middle insula) that are uniquely associated with self-reflection, and which facilitate both internal focus and sustained attention in the presence of averse (e.g. cold) external stimuli. However, the activation of brown adipose tissue (BAT) was unremarkable. Finally, forceful respiration results in increased sympathetic innervation and glucose consumption in intercostal muscle, generating heat that dissipates to lung tissue and warms circulating blood in the pulmonary capillaries. Our results provide compelling evidence for the primacy of the brain (CNS) rather than the body (peripheral mechanisms) in mediating the Iceman's responses to cold exposure. They also suggest the compelling possibility that the WHM might allow practitioners to develop higher level of control over key components of the autonomous system, with implications for lifestyle interventions that might ameliorate multiple clinical syndromes.

KEYWORDS:

CNS thermoregulation; Cold exposure; FDG PET; Functional MRI; Hydroxyephedrine PET; Periaqueductal gray; Stress-induced analgesia; Wim Hof method

4.
Aging Dis. 2018 Feb 1;9(1):109-118. doi: 10.14336/AD.2017.1025. eCollection 2018 Feb.

Alteration of Copper Fluxes in Brain Aging: A Longitudinal Study in Rodent Using 64CuCl2-PET/CT.

Peng F1,2, Xie F1, Muzik O3,4.

Author information

1
1Department of Radiology, and.
2
2Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX75390, USA.
3
3Department of Pediatrics and.
4
4 Department of Radiology, Wayne State University, Detroit, MI 48202, USA.

Abstract

Brain aging is associated with changes of various metabolic pathways. Copper is required for brain development and function, but little is known about changes in copper metabolism during brain aging. The objective of this study was to investigate alteration of copper fluxes in the aging mouse brain with positron emission tomography/computed tomography using 64CuCl2 as a radiotracer (64CuCl2-PET/CT). A longitudinal study was conducted in C57BL/6 mice (n = 5) to measure age-dependent brain and whole-body changes of 64Cu radioactivity using PET/CT after oral administration of 64CuCl2 as a radiotracer. Cerebral 64Cu uptake at 13 months of age (0.17 ± 0.05 %ID/g) was higher than the cerebral 64Cu uptake at 5 months of age (0.11 ± 0.06 %ID/g, p < 0.001), followed by decrease to (0.14 ± 0.04 %ID/g, p = 0.02) at 26 months of age. In contrast, cerebral 18F-FDG uptake was highest at 5 months of age (7.8 ± 1.2 %ID/g) and decreased to similar values at 12 (5.2 ± 1.1 %ID/g, p < 0.001) and 22 (5.6 ± 1.1 %ID/g, p < 0.001) months of age. The findings demonstrated alteration of copper fluxes associated with brain aging and the time course of brain changes in copper fluxes differed from changes in brain glucose metabolism across time, suggesting independent underlying physiological processes. Hence, age-dependent changes of cerebral copper fluxes might represent a novel metabolic biomarker for assessment of human brain aging process with PET/CT using 64CuCl2 as a radiotracer.

KEYWORDS:

Alzheimer’s disease; Positron emission tomography; brain aging; copper fluxes; copper-64 chloride; glucose metabolism

5.
Front Neurosci. 2017 Nov 16;11:640. doi: 10.3389/fnins.2017.00640. eCollection 2017.

Regulation of Brown Adipose Tissue Activity by Interoceptive CNS Pathways: The interaction between Brain and Periphery.

Author information

1
Departments of Pediatrics, Wayne State University School of Medicine, Detroit, MI, United States.
2
Radiology, Wayne State University School of Medicine, Detroit, MI, United States.
3
Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, United States.

Abstract

To maintain thermal homeostasis, specific thermogenic tissues are under the control of central thermoregulatory networks that regulate the body's response to thermal challenges. One of these mechanisms involves non-shivering thermogenesis in brown adipose tissue (BAT), which is activated in cold environments in order to defend the body against physical damage as a result of hypothermia. The objective of our study was to assess the interaction between CNS thermoregulatory pathways and sympathetic innervation in BAT during a cold exposure paradigm. Our results show that an innocuous whole-body cooling paradigm induces significant differences in fMRI BOLD signal at the location of the right anterior insula and the red nucleus/substantia nigra region, between lean subjects with high levels of sympathetic innervation in supraclavicular BAT (BAT+ group), and subjects with low levels of sympathetic innervation (BAT- group). Specifically, results indicate significantly larger fMRI BOLD signal changes between periods of cooling and warming of the skin in the BAT+ (as compared to BAT-) group at the location of the right anterior insula. In contrast, the BAT+ group showed significantly smaller fMRI BOLD signal changes in the midbrain between periods of skin cooling and warming. Our findings are consistent with a hierarchical thermoregulatory control system that involves the initiation of inhibitory signals from the right anterior insula toward midbrain areas that normally exert tonic inhibition on the medullary raphe, from where BAT is directly innervated. Our data suggests that exposure to cold elicits differential neuronal activity in interoceptive regulatory centers of subjects with high and low level of sympathetic innervation. As a result, the variability of cold-activated BAT mass observed in humans might be, in part, yoked to different sensitivities of interoceptive cortical brain areas to skin temperature changes.

KEYWORDS:

CNS thermoregulation; FDG PET; functional MRI; human brown adipose tissue; variability of BAT mass

6.
Front Neurosci. 2017 Jul 17;11:396. doi: 10.3389/fnins.2017.00396. eCollection 2017.

Reproducibility of Quantitative Brain Imaging Using a PET-Only and a Combined PET/MR System.

Author information

1
Center for Medical Physics and Biomedical Engineering, Medical University of ViennaVienna, Austria.
2
Department of Radiology, Detroit Medical Center, Children's Hospital of Michigan, Wayne State University School of MedicineDetroit, MI, United States.
3
Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of ViennaVienna, Austria.
4
Department of Clinical Physiology, Nuclear Medicine and PETRigshospitalet, Copenhagen, Denmark.
5
CBmed GmbH, Center for Biomarker Research in MedicineGraz, Austria.
6
Department for Clinical Pharmacology, Medical University of ViennaVienna, Austria.
7
Health and Environment Department, AIT Austrian Institute of Technology GmbHSeibersdorf, Austria.

Abstract

The purpose of this study was to test the feasibility of migrating a quantitative brain imaging protocol from a positron emission tomography (PET)-only system to an integrated PET/MR system. Potential differences in both absolute radiotracer concentration as well as in the derived kinetic parameters as a function of PET system choice have been investigated. Five healthy volunteers underwent dynamic (R)-[11C]verapamil imaging on the same day using a GE-Advance (PET-only) and a Siemens Biograph mMR system (PET/MR). PET-emission data were reconstructed using a transmission-based attenuation correction (AC) map (PET-only), whereas a standard MR-DIXON as well as a low-dose CT AC map was applied to PET/MR emission data. Kinetic modeling based on arterial blood sampling was performed using a 1-tissue-2-rate constant compartment model, yielding kinetic parameters (K1 and k2) and distribution volume (V T ). Differences for parametric values obtained in the PET-only and the PET/MR systems were analyzed using a 2-way Analysis of Variance (ANOVA). Comparison of DIXON-based AC (PET/MR) with emission data derived from the PET-only system revealed average inter-system differences of -33 ± 14% (p < 0.05) for the K1 parameter and -19 ± 9% (p < 0.05) for k2. Using a CT-based AC for PET/MR resulted in slightly lower systematic differences of -16 ± 18% for K1 and -9 ± 10% for k2. The average differences in V T were -18 ± 10% (p < 0.05) for DIXON- and -8 ± 13% for CT-based AC. Significant systematic differences were observed for kinetic parameters derived from emission data obtained from PET/MR and PET-only imaging due to different standard AC methods employed. Therefore, a transfer of imaging protocols from PET-only to PET/MR systems is not straightforward without application of proper correction methods. Clinical Trial Registration: www.clinicaltrialsregister.eu, identifier 2013-001724-19.

KEYWORDS:

PET; PET/MR; attenuation correction; inter-scan variability; kinetic modeling

7.
Biochem Biophys Res Commun. 2017 Jun 17;488(1):29-32. doi: 10.1016/j.bbrc.2017.04.155. Epub 2017 May 4.

Successful metformin treatment of insulin resistance is associated with down-regulation of the kynurenine pathway.

Author information

1
Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; Department of Radiology, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: otto@pet.wayne.edu.
2
Department of Food and Nutrition Science, Wayne State University School of Medicine, Detroit, MI, USA.
3
Department of Pharmacological Sciences, College of Pharmacy and Health Sciences, Wayne State University School of Medicine, Detroit, MI, USA.
4
Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
5
Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Wayne State University School of Medicine, Detroit, MI, USA.

Abstract

CONTEXT:

An extensive body of literature indicates a relationship between insulin resistance and the up-regulation of the kynurenine pathway, i.e. the preferential conversion of tryptophan to kynurenine, with subsequent overproduction of diabetogenic downstream metabolites, such as kynurenic acid.

CASE DESCRIPTION:

We have measured the concentration of kynurenine pathway metabolites (kynurenines) in the brain and pancreas of two young (27 and 28 yrs) insulin resistant, normoglycemic subjects (M-values 2 and 4 mg/kg/min, respectively) using quantitative C-11-alpha-methyl-tryptophan PET/CT imaging. Both subjects underwent a preventive 12-week metformin treatment regimen (500 mg daily) prior to the PET/CT study. Whereas treatment was successful in one of the subject (M-value increased from 2 to 12 mg/kg/min), response was poor in the other subjects (M-value changed from 4 to 5 mg/kg/min). Brain and pancreas concentrations of kynurenines observed in the responder were similar to that in a healthy control subject, whereas kynurenines determined in the non-responder were about 25% higher and similar to those found in a severely insulin resistant patient. Consistent with this outcome, M-values were negatively correlated with both kynurenic acid levels (R2 = 0.68, p = 0.09) as well as with the kynurenine to tryptophan ratio (R2 = 0.63, p = 0.11).

CONCLUSION:

The data indicates that kynurenine pathway metabolites are increased in subjects with insulin resistance prior to overt manifestation of hyperglycemia. Moreover, successful metformin treatment leads to a normalization of tryptophan metabolism, most likely as a result of decreased contribution from the kynurenine metabolic pathway.

KEYWORDS:

AMT PET imaging; Insulin resistance; Kynurenine pathway; Tryptophan metabolism

PMID:
28478038
PMCID:
PMC5554450
DOI:
10.1016/j.bbrc.2017.04.155
[Indexed for MEDLINE]
Free PMC Article
Icon for Elsevier Science Icon for PubMed Central
8.
Metab Brain Dis. 2017 Jun;32(3):717-726. doi: 10.1007/s11011-017-9956-9. Epub 2017 Jan 27.

Age-dependent changes of cerebral copper metabolism in Atp7b -/- knockout mouse model of Wilson's disease by [64Cu]CuCl2-PET/CT.

Author information

1
Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9140, USA.
2
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
3
Carman & Ann Adams Department of Pediatrics, Wayne State University, Detroit, MI, USA.
4
Department of Radiology, School of Medicine, Wayne State University, Detroit, MI, USA.
5
Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9140, USA. Fangyu.Peng@UTSouthwestern.edu.
6
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. Fangyu.Peng@UTSouthwestern.edu.

Abstract

Copper is a nutritional metal required for brain development and function. Wilson's disease (WD), or hepatolenticular degeneration, is an inherited human copper metabolism disorder caused by a mutation of the ATP7B gene. Many WD patients present with variable neurological and psychiatric symptoms, which may be related to neurodegeneration secondary to copper metabolism imbalance. The objective of this study was to explore the feasibility and use of copper-64 chloride ([64C]CuCl2) as a tracer for noninvasive assessment of age-dependent changes of cerebral copper metabolism in WD using an Atp7b -/- knockout mouse model of WD and positron emission tomography/computed tomography (PET/CT) imaging. Continuing from our recent study of biodistribution and radiation dosimetry of [64C]CuCl2 in Atp7b -/- knockout mice, PET quantitative analysis revealed low 64Cu radioactivity in the brains of Atp7b -/- knockout mice at 7th weeks of age, compared with 64Cu radioactivity in the brains of age- and gender-matched wild type C57BL/6 mice, at 24 h (h) post intravenous injection of [64C]CuCl2 as a tracer. Furthermore, age-dependent increase of 64Cu radioactivity was detected in the brains of Atp7b -/- knockout mice from the 13th to 21th weeks of age, based on the data derived from a longitudinal [64C]CuCl2-PET/CT study of Atp7b -/- knockout mice with orally administered [64Cu]CuCl2 as a tracer. The findings of this study support clinical use of [64Cu]CuCl2-PET/CT imaging as a tool for noninvasive assessment of age-dependent changes of cerebral copper metabolism in WD patients presenting with variable neurological and psychiatric symptoms.

KEYWORDS:

Atp7b gene; Copper metabolism; Copper-64 chloride; Neurodegeneration; Positron emission tomography; Wilson’s disease

PMID:
28130615
PMCID:
PMC5573586
DOI:
10.1007/s11011-017-9956-9
[Indexed for MEDLINE]
Free PMC Article
Icon for Springer Icon for PubMed Central
9.
J Nucl Med. 2017 May;58(5):799-806. doi: 10.2967/jnumed.116.180992. Epub 2016 Oct 27.

Sympathetic Innervation of Cold-Activated Brown and White Fat in Lean Young Adults.

Author information

1
Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan otto@pet.wayne.edu.
2
Department of Radiology, Wayne State University School of Medicine, Detroit, Michigan.
3
Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan.
4
Department of Anthropology, Northwestern University, Evanston, Illinois.
5
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan; and.
6
Center for Integrative Metabolic and Endocrine Research and Family Medicine.

Abstract

Recent work in rodents has demonstrated that basal activity of the local sympathetic nervous system is critical for maintaining brown adipocyte phenotypes in classic brown adipose tissue (BAT) and white adipose tissue (WAT). Accordingly, we sought to assess the relationship between sympathetic innervation and cold-induced activation of BAT and WAT in lean young adults. Methods: Twenty adult lean normal subjects (10 women and 10 men; mean age ± SD, 23.3 ± 3.8 y; body mass index, 23.7 ± 2.5 kg/m2) underwent 11C-meta-hydroxyephedrin (11C-HED) and 15O-water PET imaging at rest and after exposure to mild cold (16°C) temperature. In addition, 18F-FDG images were obtained during the cold stress condition to assess cold-activated BAT mass. Subjects were divided into 2 groups (high BAT and low BAT) based on the presence of 18F-FDG tracer uptake. Blood flow and 11C-HED retention index (RI, an indirect measure of sympathetic innervation) were calculated from dynamic PET scans at the location of BAT and WAT. Whole-body daily energy expenditure (DEE) during rest and cold stress was measured by indirect calorimetry. Tissue level oxygen consumption (MRO2) was determined and used to calculate the contribution of cold-activated BAT and WAT to daily DEE. Results:18F-FDG uptake identified subjects with high and low levels of cold-activated BAT mass (high BAT, 96 ± 37 g; low-BAT, 16 ± 4 g). 11C-HED RI under thermoneutral conditions significantly predicted 18F-FDG uptake during cold stress (R2 = 0.68, P < 0.01). In contrast to the significant increase of 11C-HED RI during cold in BAT (2.42 ± 0.85 vs. 3.43 ± 0.93, P = 0.02), cold exposure decreased the 11C-HED RI in WAT (0.44 ± 0.22 vs. 0.41 ± 0.18) as a consequence of decreased perfusion (1.22 ± 0.20 vs. 1.12 ± 0.16 mL/100 g/min). The contribution of WAT to whole-body DEE was approximately 150 kcal/d at rest (149 ± 52 kcal/d), which decreased to approximately 100 kcal/d during cold (102 ± 47 kcal/d). Conclusion: The level of sympathetic innervation, as determined by 11C-HED RI, can predict levels of functional BAT. Overall, blood flow is the best independent predictor of 11C-HED RI and 18F-FDG uptake across thermoneutral and cold conditions. In contrast to BAT, cold stress reduces blood flow and 18F-FDG uptake in subcutaneous WAT, indicating that the physiologic response is to reduce heat loss rather than to generate heat.

KEYWORDS:

HED PET imaging; brown fat; subcutaneous fat; sympathetic innervation

PMID:
27789721
PMCID:
PMC5414500
DOI:
10.2967/jnumed.116.180992
[Indexed for MEDLINE]
Free PMC Article
Icon for HighWire Icon for PubMed Central
10.
J Nucl Med. 2017 Feb;58(2):208-213. doi: 10.2967/jnumed.116.179994. Epub 2016 Oct 20.

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-18F-Fluoroethyl)-l-Tryptophan and α-11C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts.

Author information

1
Department of Neurosurgery, Wayne State University, Detroit, Michigan.
2
Department of Pediatrics, Wayne State University, Detroit, Michigan.
3
Department of Radiology, Wayne State University, Detroit, Michigan.
4
PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan.
5
Department of Oncology, Wayne State University, Detroit, Michigan.
6
Karmanos Cancer Institute, Detroit, Michigan.
7
Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern, Dallas, Texasand.
8
Department of Neurology, Wayne State University, Detroit, Michigan.
9
Department of Neurosurgery, Wayne State University, Detroit, Michigan smittal@med.wayne.edu.

Abstract

Abnormal tryptophan metabolism via the kynurenine pathway is involved in the pathophysiology of a variety of human diseases including cancers. α-11C-methyl-l-tryptophan (11C-AMT) PET imaging demonstrated increased tryptophan uptake and trapping in epileptic foci and brain tumors, but the short half-life of 11C limits its widespread clinical application. Recent in vitro studies suggested that the novel radiotracer 1-(2-18F-fluoroethyl)-l-tryptophan (18F-FETrp) may be useful to assess tryptophan metabolism via the kynurenine pathway. In this study, we tested in vivo organ and tumor uptake and kinetics of 18F-FETrp in patient-derived xenograft mouse models and compared them with 11C-AMT uptake.

METHODS:

Xenograft mouse models of glioblastoma and metastatic brain tumors (from lung and breast cancer) were developed by subcutaneous implantation of patient tumor fragments. Dynamic PET scans with 18F-FETrp and 11C-AMT were obtained for mice bearing human brain tumors 1-7 d apart. The biodistribution and tumoral SUVs for both tracers were compared.

RESULTS:

18F-FETrp showed prominent uptake in the pancreas and no bone uptake, whereas 11C-AMT showed higher uptake in the kidneys. Both tracers showed uptake in the xenograft tumors, with a plateau of approximately 30 min after injection; however, 18F-FETrp showed higher tumoral SUV than 11C-AMT in all 3 tumor types tested. The radiation dosimetry for 18F-FETrp determined from the mouse data compared favorably with the clinical 18F-FDG PET tracer.

CONCLUSION:

18F-FETrp tumoral uptake, biodistribution, and radiation dosimetry data provide strong preclinical evidence that this new radiotracer warrants further studies that may lead to a broadly applicable molecular imaging tool to examine abnormal tryptophan metabolism in human tumors.

KEYWORDS:

brain metastasis; glioblastoma; indoleamine 2,3-dioxygenase

PMID:
27765857
PMCID:
PMC5288739
DOI:
10.2967/jnumed.116.179994
[Indexed for MEDLINE]
Free PMC Article
Icon for HighWire Icon for PubMed Central
11.
Hum Brain Mapp. 2016 Sep;37(9):3188-202. doi: 10.1002/hbm.23233. Epub 2016 May 24.

In vivo correlates of thermoregulatory defense in humans: Temporal course of sub-cortical and cortical responses assessed with fMRI.

Author information

1
Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan, 48201.
2
Department of Radiology, Wayne State University School of Medicine, Detroit, Michigan, 48201.
3
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, 48201.

Abstract

Extensive studies in rodents have established the role of neural pathways that are activated during thermoregulation. However, few studies have been conducted in humans to assess the complex, hierarchically organized thermoregulatory network in the CNS that maintains thermal homeostasis, especially as it pertains to cold exposure. To study the human thermoregulatory network during whole body cold exposure, we have used functional MRI to characterize changes in the BOLD signal within the constituents of the thermoregulatory network in 20 young adult controls during non-noxious cooling and rewarming of the skin by a water-perfused body suit. Our results indicate significant decreases of BOLD signal during innocuous whole body cooling stimuli in the midbrain, the right anterior insula, the right anterior cingulate, and the right inferior parietal lobe. Whereas brain activation in these areas decreased during cold exposure, brain activation increased significantly in the bilateral orbitofrontal cortex during this period. The BOLD signal time series derived from significant activation sites in the orbitofrontal cortex showed opposed phase to those observed in the other brain regions, suggesting complementary processing mechanisms during mild hypothermia. The significance of our findings lies in the recognition that whole body cooling evokes a response in a hierarchically organized thermoregulatory network that distinguishes between cold and warm stimuli. This network seems to generate a highly resolved interoceptive representation of the body's condition that provides input to the orbitofrontal cortex, where higher-order integration takes place and invests internal states with emotional significance that motivate behavior. Hum Brain Mapp 37:3188-3202, 2016.

KEYWORDS:

cold stress; fMRI; insula; midbrain; orbitofrontal cortex; thermoregulation

PMID:
27220041
DOI:
10.1002/hbm.23233
[Indexed for MEDLINE]
Icon for Wiley
12.
Mol Imaging. 2016 May 5;15. pii: 1536012116644881. doi: 10.1177/1536012116644881. Print 2016.

Tryptophan PET Imaging of the Kynurenine Pathway in Patient-Derived Xenograft Models of Glioblastoma.

Author information

1
Department of Neurosurgery, Wayne State University, Detroit, MI, USA Department of Oncology, Wayne State University, Detroit, MI, USA.
2
Department of Neurosurgery, Wayne State University, Detroit, MI, USA.
3
Department of Pathology, Wayne State University, Detroit, MI, USA Karmanos Cancer Institute, Detroit, MI, USA.
4
Department of Pediatrics, Wayne State University, Detroit, MI, USA Department of Radiology, Wayne State University, Detroit, MI, USA PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, MI, USA.
5
Karmanos Cancer Institute, Detroit, MI, USA Department of Pediatrics, Wayne State University, Detroit, MI, USA PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, MI, USA Department of Neurology, Wayne State University, Detroit, MI, USA.
6
Department of Neurosurgery, Wayne State University, Detroit, MI, USA Department of Oncology, Wayne State University, Detroit, MI, USA Karmanos Cancer Institute, Detroit, MI, USA smittal@med.wayne.edu.

Abstract

Increasing evidence demonstrates the immunosuppressive kynurenine pathway's (KP) role in the pathophysiology of human gliomas. To study the KP in vivo, we used the noninvasive molecular imaging tracer α-[(11)C]-methyl-l-tryptophan (AMT). The AMT-positron emission tomography (PET) has shown high uptake in high-grade gliomas and predicted survival in patients with recurrent glioblastoma (GBM). We generated patient-derived xenograft (PDX) models from dissociated cells, or tumor fragments, from 5 patients with GBM. Mice bearing subcutaneous tumors were imaged with AMT-PET, and tumors were analyzed to detect the KP enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, tryptophan 2,3-dioxygenase, kynureninase, and kynurenine 3-monooxygenase. Overall, PET imaging showed robust tumoral AMT uptake in PDX mice with prolonged tracer accumulation over 60 minutes, consistent with AMT trapping seen in humans. Immunostained tumor tissues demonstrated positive detection of multiple KP enzymes. Furthermore, intracranial implantation of GBM cells was performed with imaging at both 9 and 14 days postimplant, with a marked increase in AMT uptake at 14 days and a corresponding high level of tissue immunostaining for KP enzymes. These results indicate that our PDX mouse models recapitulate human GBM, including aberrant tryptophan metabolism, and offer an in vivo system for development of targeted therapeutics for patients with GBM.

KEYWORDS:

indoleamine 2,3-dioxygenase; orthotopic mouse model; patient-derived xenograft; tryptophan 2,3-dioxygenase; α-[11C]-methyl-l-tryptophan

PMID:
27151136
PMCID:
PMC4887573
DOI:
10.1177/1536012116644881
[Indexed for MEDLINE]
Free PMC Article
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13.
J Pediatr. 2016 Mar;170:45-53.e1-4. doi: 10.1016/j.jpeds.2015.11.033. Epub 2015 Dec 30.

Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A Randomized Trial.

Author information

1
Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI; Children's Hospital of Michigan, Detroit, MI. Electronic address: Diane.Chugani@nemours.org.
2
Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI; Children's Hospital of Michigan, Detroit, MI; Department of Neurology, Wayne State University School of Medicine, Detroit, MI.
3
Neuroscience Institute, University Hospitals Case Medical Center, Rainbow Babies and Children's Hospital, Cleveland, OH.
4
Cleveland Clinic Neurogenetics & Metabolism, Neuroscience Institute Lerner College of Medicine-Case Western Reserve University, Cleveland, OH.
5
Departments of Neurology and Pediatrics, University of Texas Southwestern Medical Center, Children's Medical Center of Dallas, Dallas, TX.
6
Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Department of Pediatrics, University of California Davis, Davis, CA.
7
Department of Neurology, New York University Langone Medical Center, New York, NY; Department of Child and Adolescent Psychiatry, New York University Langone Medical Center, New York, NY.
8
Department of Family Medicine and Public Health Sciences, Wayne State University School of Medicine, Detroit, MI.
9
Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI.
10
Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI; Children's Hospital of Michigan, Detroit, MI.
11
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI.
12
Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI; Children's Hospital of Michigan, Detroit, MI; Department of Neurology, Wayne State University School of Medicine, Detroit, MI; Department of Radiology, Wayne State University School of Medicine, Detroit, MI.
13
School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada.
14
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.

Abstract

OBJECTIVES:

To determine safety and efficacy of the 5HT1A serotonin partial agonist buspirone on core autism and associated features in children with autism spectrum disorder (ASD).

STUDY DESIGN:

Children 2-6 years of age with ASD (N = 166) were randomized to receive placebo or 2.5 or 5.0 mg of buspirone twice daily. The primary objective was to evaluate the effects of 24 weeks of buspirone on the Autism Diagnostic Observation Schedule (ADOS) Composite Total Score. Secondary objectives included evaluating the effects of buspirone on social competence, repetitive behaviors, language, sensory dysfunction, and anxiety and to assess side effects. Positron emission tomography measures of tryptophan metabolism and blood serotonin concentrations were assessed as predictors of buspirone efficacy.

RESULTS:

There was no difference in the ADOS Composite Total Score between baseline and 24 weeks among the 3 treatment groups (P = .400); however, the ADOS Restricted and Repetitive Behavior score showed a time-by-treatment effect (P = .006); the 2.5-mg buspirone group showed significant improvement (P = .003), whereas placebo and 5.0-mg buspirone groups showed no change. Children in the 2.5-mg buspirone group were more likely to improve if they had fewer foci of increased brain tryptophan metabolism on positron emission tomography (P = .018) or if they showed normal levels of blood serotonin (P = .044). Adverse events did not differ significantly among treatment groups.

CONCLUSIONS:

Treatment with 2.5 mg of buspirone in young children with ASD might be a useful adjunct therapy to target restrictive and repetitive behaviors in conjunction with behavioral interventions.

TRIAL REGISTRATION:

ClinicalTrials.gov: NCT00873509.

PMID:
26746121
DOI:
10.1016/j.jpeds.2015.11.033
[Indexed for MEDLINE]
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14.
J Biomater Appl. 2016 Feb;30(7):908-18. doi: 10.1177/0885328215608335. Epub 2015 Dec 15.

Flow perfusion culture of MC3T3-E1 osteogenic cells on gradient calcium polyphosphate scaffolds with different pore sizes.

Author information

1
Department of Biomedical Engineering, Wayne State University, USA.
2
Detroit Medical Center & Providence Hospital Orthopaedic Residency, USA Department of Orthopaedic Surgery, Providence Hospital and Medical Centers, USA.
3
PET Center, Wayne State University, USA.
4
Department of Biomedical Engineering, Wayne State University, USA Department of Orthopaedic Surgery, Providence Hospital and Medical Centers, USA as7606@wayne.edu.

Abstract

Calcium polyphosphate is a biodegradable bone substitute. It remains a challenge to prepare porous calcium polyphosphate with desired gradient porous structures. In this study, a modified one-step gravity sintering method was used to prepare calcium polyphosphate scaffolds with desired-gradient-pore-size distribution. The differences of porous structure, mechanical strength, and degradation rate between gradient and homogenous calcium polyphosphate scaffolds were evaluated by micro-computed tomography, scanning electron microscopy, and mechanical testing. Preosteoblastic MC3T3-E1 cells were seeded onto gradient and homogenous calcium polyphosphate scaffolds and cultured in a flow perfusion bioreactor. The distribution, proliferation, and differentiation of the MC3T3-E1 cells were compared to that of homogenous calcium polyphosphate scaffolds. Though no significant difference of cell proliferation was found between the gradient and the homogenous calcium polyphosphate scaffolds, a much higher cell differentiation and mineralization were observed in the gradient calcium polyphosphate scaffolds than that of the homogenous calcium polyphosphate scaffolds, as manifested by increased alkaline phosphatase activity (p < 0.05). The improved distribution and differentiation of cultured cells within gradient scaffolds were further supported by both (18)F-fluorine micro-positron emission tomography scanning and in vitro tetracycline labeling. We conclude that the calcium polyphosphate scaffold with gradient pore sizes enhances osteogenic cell differentiation as well as mineralization. The in vivo performance of gradient calcium polyphosphate scaffolds warrants further investigation in animal bone defect models.

KEYWORDS:

18F-fluorine micro-positron emission tomography; Calcium polyphosphate; gradient scaffold; perfusion flow bioreactor

PMID:
26675750
DOI:
10.1177/0885328215608335
[Indexed for MEDLINE]
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15.
J Nucl Med. 2015 Aug;56(8):1252-7. doi: 10.2967/jnumed.115.154575. Epub 2015 Jun 25.

Assessment of Traumatic Brain Injury by Increased 64Cu Uptake on 64CuCl2 PET/CT.

Author information

1
Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas fangyu.peng@utsouthwestern.edu.
2
Carman and Ann Adams Department of Pediatrics, School of Medicine, Wayne State University, Detroit, Michigan Department of Radiology, School of Medicine, Wayne State University, Detroit, Michigan.
3
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
4
Department of Pediatrics and Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York; and.
5
Center for Neurosciences and Regenerative Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

Abstract

Copper is a nutritional trace element required for cell proliferation and wound repair.

METHODS:

To explore increased copper uptake as a biomarker for noninvasive assessment of traumatic brain injury (TBI), experimental TBI in C57BL/6 mice was induced by controlled cortical impact, and (64)Cu uptake in the injured cortex was assessed with (64)CuCl2 PET/CT.

RESULTS:

At 24 h after intravenous injection of the tracer, uptake was significantly higher in the injured cortex of TBI mice (1.15 ± 0.53 percentage injected dose per gram of tissue [%ID/g]) than in the uninjured cortex of mice without TBI (0.53 ± 0.07 %ID/g, P = 0.027) or the cortex of mice that received an intracortical injection of zymosan A (0.62 ± 0.22 %ID/g, P = 0.025). Furthermore, uptake in the traumatized cortex of untreated TBI mice (1.15 ± 0.53 %ID/g) did not significantly differ from that in minocycline-treated TBI mice (0.93 ± 0.30 %ID/g, P = 0.33).

CONCLUSION:

Overall, the data suggest that increased (64)Cu uptake in traumatized brain tissues holds potential as a new biomarker for noninvasive assessment of TBI with (64)CuCl2 PET/CT.

KEYWORDS:

64Cu-chloride; copper metabolism; neuroimaging; positron emission tomography; traumatic brain injury

PMID:
26112025
PMCID:
PMC4583785
DOI:
10.2967/jnumed.115.154575
[Indexed for MEDLINE]
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16.
Neuro Oncol. 2015 Sep;17(9):1284-92. doi: 10.1093/neuonc/nov098. Epub 2015 Jun 18.

Molecular imaging correlates of tryptophan metabolism via the kynurenine pathway in human meningiomas.

Author information

1
Department of Pediatrics, Wayne State University, Detroit, Michigan (E.B., D.O.K., O.M., C.J.); Department of Neurology, Wayne State University, Detroit, Michigan (C.J.); Department of Neurosurgery, Wayne State University, Detroit, Michigan (A.R.G., K.V., S.K.M., S.M.); Department of Oncology, Wayne State University, Detroit, Michigan (A.R.G., S.M.); Department of Radiology, Wayne State University, , Detroit, Michigan (N.L.R., O.M.); Department of Pathology, Wayne State University, Detroit, Michigan (W.J.K.); PET Center, Children's Hospital of Michigan, Detroit, Michigan (E.B., D.O.K., O.M., C.J.); Karmanos Cancer Institute, Detroit, Michigan (N.L.R., W.J.K., S.M., C.J.).

Abstract

BACKGROUND:

Increased tryptophan metabolism via the kynurenine pathway (KP) is a key mechanism of tumoral immune suppression in gliomas. However, details of tryptophan metabolism in meningiomas have not been elucidated. In this study, we evaluated in vivo tryptophan metabolism in meningiomas and compared it with gliomas using α-[(11)C]-methyl-L-tryptophan (AMT)-PET. We also explored expression patterns of KP enzymes in resected meningiomas.

METHODS:

Forty-seven patients with MRI-detected meningioma (n = 16) and glioma (n = 31) underwent presurgical AMT-PET scanning. Tumoral AMT uptake and tracer kinetic parameters (including K and k3' evaluating unidirectional uptake and trapping, respectively) were measured, correlated with meningioma grade, and compared between meningiomas and gliomas. Patterns of KP enzyme expression were assessed by immunohistochemistry in all meningiomas.

RESULTS:

Meningioma grade showed a positive correlation with AMT k3' tumor/cortex ratio (r = 0.75, P = .003), and this PET parameter distinguished grade I from grade II/III meningiomas with 92% accuracy. Kinetic AMT parameters could differentiate meningiomas from both low-grade gliomas (97% accuracy by k3' ratios) and high-grade gliomas (83% accuracy by K ratios). Among 3 initial KP enzymes (indoleamine 2,3-dioxygenase 1/2, and tryptophan 2,3-dioxygenase 2 [TDO2]), TDO2 showed the strongest immunostaining, particularly in grade I meningiomas. TDO2 also showed a strong negative correlation with AMT k3' ratios (P = .001).

CONCLUSIONS:

PET imaging of tryptophan metabolism can provide quantitative imaging markers for differentiating grade I from grade II/III meningiomas. TDO2 may be an important driver of in vivo tryptophan metabolism in these tumors. These results can have implications for pharmacological targeting of the KP in meningiomas.

KEYWORDS:

glioma; indoleamine 2,3-dioxygenase (IDO); meningioma; positron emission tomography (PET); tryptophan 2,3-dioxygenase (TDO)

PMID:
26092774
PMCID:
PMC4588760
DOI:
10.1093/neuonc/nov098
[Indexed for MEDLINE]
Free PMC Article
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17.
Physiol Rep. 2015 Jan 19;3(1). pii: e12262. doi: 10.14814/phy2.12262. Print 2015 Jan 1.

Plasma irisin in runners and nonrunners: no favorable metabolic associations in humans.

Author information

1
Oakland University, Rochester, Michigan, USA.
2
Wayne State University, Detroit, Michigan, USA.

Abstract

Irisin is a hormone which mimics the favorable metabolic effects associated with regular exercise, by converting subcutaneous white fat into brownish fat, in rodents. Thirty-three human subjects (16 runners, 17 nonrunners) were measured for: resting energy expenditure (REE), body composition, VO2 Peak test, [irisin]p, and plasma metabolic profile. Nine female nonrunners then participated in a 10-week supervised 5 km training program and tested after the race. Two runners underwent (18)F-FDG-PET scans to quantify brown fat. No gender or age (28 ± 10 years) differences noted between matched cohorts. Runners averaged 58 ± 26 miles/week for 13 ± 6 years and had lower bodyweight (63 vs. 88 kg; P < 0.001), BMI (21 vs. 30 kg/m(2); P < 0.0001), triglycerides (58 vs. 123 mg/dL; P < 0.01), total (white) fat (14 vs. 32%; P < 0.0001), and had higher VO2 Peak (63 vs. 34 mL/kg-min; P < 0.0001) and HDL (65 vs. 48 mg/dL; P < 0.01) compared with nonrunners. [Irisin]p was lower in runners versus nonrunners both before (179 vs. 197 ng/mL; NS) and after (207 vs. 226 ng/mL; NS) the VO2 Peak test. Significant (P < 0.05) positive correlations were noted between [irisin]p versus BMI (r(2) = 0.15), triglycerides (r(2) = 0.40), and total body fat(g) (r(2) = 0.24) with a significant negative correlation between [irisin]p versus respiratory quotient (r(2) = 0.33). Total lean mass significantly correlated with REE (r(2) = 0.58) while total fat mass inversely correlated with VO2 Peak (r(2) = 0.64). Nonrunners had lower [irisin]p after completion of the training program (194 vs.181 ng/mL; pre- to post-training; P > 0.05). Neither runner selected for (18)F-FDG-PET scans had brown fat. Runners demonstrated significantly healthier metabolic and body composition profiles compared with nonrunners. None of these favorable exercise effects were positively associated with [irisin]p..

KEYWORDS:

Brown fat; energy expenditure; running

18.
Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):E4910. doi: 10.1073/pnas.1418398111. Epub 2014 Nov 10.

Reply to Skoyles: Decline in growth rate, not muscle mass, predicts the human childhood peak in brain metabolism.

Author information

1
Department of Anthropology, Institute for Policy Research, Northwestern University, Evanston, IL 60208; kuzawa@northwestern.edu.
2
Positron Emission Tomography Center, Children's Hospital of Michigan, Detroit, MI 48201; Departments of Pediatrics and Neurology and.
3
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201;
4
Neurology and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201;
5
Departments of Pediatrics and.
6
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
7
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201; Institute for Genomic Biology, Department of Molecular and Integrative Physiology, University of Illinois, Urbana, IL 61801; and.
8
Department of Anthropology, The George Washington University, Washington, DC 20052; and.
9
Department of Anthropology.
10
Departments of Psychiatry and Biostatistics, Harvard University and McLean Hospital, Cambridge, MA 02138.
PMID:
25385651
PMCID:
PMC4246347
DOI:
10.1073/pnas.1418398111
[Indexed for MEDLINE]
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19.
ACS Med Chem Lett. 2014 Aug 19;5(10):1152-5. doi: 10.1021/ml500285t. eCollection 2014 Oct 9.

Radiosynthesis of (11)C-Levetiracetam: A Potential Marker for PET Imaging of SV2A Expression.

Author information

1
PET Center, Children's Hospital of Michigan, Detroit Medical Center , Detroit, Michigan 48201, United States ; Departments of Pediatrics, Radiology, and Neurology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States ; Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center , Dallas, Texas 75390, United States ; Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center , Dallas, Texas 75390, United States.
2
PET Center, Children's Hospital of Michigan, Detroit Medical Center , Detroit, Michigan 48201, United States ; Departments of Pediatrics, Radiology, and Neurology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States ; Departments of Pediatrics, Radiology, and Neurology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
3
PET Center, Children's Hospital of Michigan, Detroit Medical Center , Detroit, Michigan 48201, United States ; Departments of Pediatrics, Radiology, and Neurology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States ; Departments of Pediatrics, Radiology, and Neurology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States ; Departments of Pediatrics, Radiology, and Neurology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
4
Departments of Nuclear Medicine and Oncology, Fudan University Shanghai Cancer Center , Shanghai 200032, People's Republic of China ; Departments of Nuclear Medicine and Oncology, Fudan University Shanghai Cancer Center , Shanghai 200032, People's Republic of China.

Abstract

The multistep preparation of (11)C-levetiracetam ((11)C-LEV) was carried out by a one-pot radiosynthesis with 8.3 ± 1.6% (n = 8) radiochemical yield in 50 ± 5.0 min. Briefly, the propionaldehyde was converted to propan-1-imine in situ as labeling precursor by incubation with ammonia. Without further separation, the imine was reacted with (11)C-HCN to form (11)C-aminonitrile. This crude was then reacted with 4-chlorobutyryl chloride and followed by hydrolysis to yield (11)C-LEV after purification by chiral high-performance liquid chromatography (HPLC). Both the radiochemical and enantiomeric purities of (11)C-LEV were >98%.

KEYWORDS:

Levetiracetam; carbon-11; positron emission tomography; synaptic vesicle protein 2A

20.
J Nucl Med. 2014 Oct;55(10):1605-10. doi: 10.2967/jnumed.114.141002. Epub 2014 Sep 4.

Clinical significance of tryptophan metabolism in the nontumoral hemisphere in patients with malignant glioma.

Author information

1
PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan Department of Pediatrics, Wayne State University, Detroit, Michigan.
2
PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan.
3
Department of Radiology, Wayne State University, Detroit, Michigan Karmanos Cancer Institute, Detroit, Michigan.
4
PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan Department of Pediatrics, Wayne State University, Detroit, Michigan Department of Radiology, Wayne State University, Detroit, Michigan Department of Neurology, Wayne State University, Detroit, Michigan.
5
PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan Department of Radiology, Wayne State University, Detroit, Michigan.
6
Karmanos Cancer Institute, Detroit, Michigan.
7
Karmanos Cancer Institute, Detroit, Michigan Department of Neurology, Wayne State University, Detroit, Michigan.
8
Karmanos Cancer Institute, Detroit, Michigan Department of Neurosurgery, Wayne State University, Detroit, Michigan; and Department of Oncology, Wayne State University, Detroit, Michigan.
9
PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan Department of Pediatrics, Wayne State University, Detroit, Michigan Karmanos Cancer Institute, Detroit, Michigan Department of Neurology, Wayne State University, Detroit, Michigan juhasz@pet.wayne.edu.

Abstract

α-(11)C-methyl-L-tryptophan (AMT) PET allows evaluation of brain serotonin synthesis and can also track upregulation of the immunosuppressive kynurenine pathway in tumor tissue. Increased AMT uptake is a hallmark of World Health Organization grade III-IV gliomas. Our recent study also suggested decreased frontal cortical AMT uptake in glioma patients contralateral to the tumor. The clinical significance of extratumoral tryptophan metabolism has not been established. In the present study, we investigated clinical correlates of tryptophan metabolic abnormalities in the nontumoral hemisphere of glioma patients.

METHODS:

Standardized AMT uptake values (SUVs) and the uptake rate constant of AMT (K [mL/g/min], a measure proportional to serotonin synthesis in nontumoral gray matter) were quantified in the frontal and temporal cortex and thalamus in the nontumoral hemisphere in 77 AMT PET scans of 66 patients (41 men, 25 women; mean age ± SD, 55 ± 15 y) with grade III-IV gliomas. These AMT values were determined before treatment in 35 and after treatment in 42 patients and were correlated with clinical variables and survival.

RESULTS:

AMT uptake in the thalamus showed a moderate age-related increase before treatment (SUV, r = 0.39, P = 0.02) but decrease after treatment (K, r = -0.33, P = 0.057). Women had higher thalamic SUVs before treatment (P = 0.037) and higher thalamic (P = 0.013) and frontal cortical K values (P = 0.023) after treatment. In the posttreatment glioma group, high thalamic SUVs and high thalamocortical SUV ratios were associated with short survival in Cox regression analysis. The thalamocortical ratio remained strongly prognostic (P < 0.01) when clinical predictors, including age, glioma grade, and time since radiotherapy, were entered in the regression model. Long interval between radiotherapy and posttreatment AMT PET as well as high radiation dose affecting the thalamus were associated with lower contralateral thalamic or cortical AMT uptake values.

CONCLUSION:

These observations provide evidence for altered tryptophan uptake in contralateral cortical and thalamic brain regions in glioma patients after initial therapy, suggesting treatment effects on the serotonergic system. Low thalamic tryptophan uptake appears to be a strong, independent predictor of long survival in patients with previous glioma treatment.

KEYWORDS:

PET; brain; glioma; survival; tryptophan metabolism

PMID:
25189339
PMCID:
PMC4303620
DOI:
10.2967/jnumed.114.141002
[Indexed for MEDLINE]
Free PMC Article
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